Toxicokinetics through

Two problems with PbB versus reproductive and fetal harm relationships are (1) the sensitivity of current dose—responses in terms of both intensity and time course of Pb exposures and (2) the dynamic, labile nature of bone Ca resorption, associated bone Pb release, and Pb toxicokinetics through the course of pregnancy, especially in the third trimester. 

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily seen that pK is also a pH value at which 50% of the compound exists in ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chemical through the biological membranes is greatly impaired, and this attenuates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stomach. 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

There are several points along the pathway to hazard that can be influenced through molecular design that are described in more detail later in this chapter. The magnitude and duration of a toxic event can be minimized through influencing the toxicodynamic and toxicokinetic phases associated with the manifestation of toxicity. 

Baud, F.J., P. Houze, C. Bismuth, J.M. Scherrmann, A. Jaeger, and C. Keyes. 1988. Toxicokinetics of paraquat through the heart-lung block. Six cases of acute human poisoning. Jour. Toxicol. Clin. Toxicol. 26 35-50. Bauer, C.A. 1983. The Effects of Paraquat on Various Reproductive and Growth Parameters in First and Second Generation Bobwhite Quail. Ph.D. thesis, Indiana State Univ., Terre Haute. 70 pp. 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

The merit of this definition is that it distinguishes factors controlling the toxicokinetics of the substance (i.e., the rates of uptake, elimination, transformation, and internal distribution) from environmental factors (external to the organism) that control the amount of chemical that can be absorbed by the organism through a specific route of uptake. 

As is apparent from Figure 3-6, there are minimal data on health effects following dermal absorption. In addition, there were only two studies on toxicokinetics that used the dermal exposure route. Although there are several animal studies that evaluated the health effects of DEHP through the respiratory route, these studies are also limited in scope. In each case, exposures were at very low levels and without effect. Although the exposure concentrations were relevant to human exposures through inhalation, the lack of observed effects makes it difficult to evaluate whether there are specific risks that apply to respiratory exposures. 

In the mechanistic models used to predict toxic effects of time-variable exposure to organisms, a distinction can be made between 1-step models and 2-step models (Ashauer et al. 2006). One-step models only consider toxicokinetics, whereas 2-step models consider both toxicokinetics and toxicodynamics. One-step models try to describe the uptake and elimination of a given compound in an organism and relate the calculated internal concentration to the effect occurring. Usually, an average total body residue is calculated, assuming that the concentration at the actual site(s) of action will be linearly related to the total body concentration. In specific cases, it may be necessary to calculate the concentration at the site of action through the use of more refined multicompartment (PBPK) models. 

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